chr3-37011867-G-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.588+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000249.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.588+5 nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9536098, 15713769, 16341550, 17576681, 18561205, 24090359). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 32363481). ClinVar contains an entry for this variant (Variation ID: 851243). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28874130, 32363481; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 7 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. It affects a nucleotide within the consensus splice site. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.588+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 7 in the MLH1 gene. This alteration has been reported in a Latin American family that fulfilled Amsterdam criteria or Bethesda guidelines (Rossi BM et al. BMC Cancer. 2017 Sep 5;17(1):623). This alteration has been detected as a somatic alteration in a colorectal cancer which was MSI-H and showed loss of MLH1 by IHC. RNA studies demonstrated skipping of coding exon 7, leading to non-functional RNA (Lefevre JH et al. Fam Cancer. 2010 Dec;9(4):589-94). In addition, a similar alteration at this position, c.588+5G>A, has also been shown to lead to the skipping of coding exon 7 and a truncated protein product (Pagenstecher C et al. Hum. Genet., 2006 Mar;119:9-22; Tournier et al. Human Mutation. 2008. 29(12),1412-1424; Petersen SM et al. BMC Medical Genetics 2013,14:103).This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to significantly weaken the native donor splice site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at